Mitochondrial proton leak and neonatal brain injury

总结 新生儿脑损伤，即缺氧缺血性（HI）脑损伤是导致新生儿残疾的主要原因之一。 孩子线粒体功能障碍，由于激活的渗透性转换孔（mPTP）已牵连 在HI损伤后的细胞死亡中，但仅在成熟脑中。有人提出mPTP是非特异性的 质子/离子穿过线粒体内膜泄漏，这耗散了质子动力并使质子/离子穿过线粒体内膜。 线粒体缺乏或不能产生ATP，通常导致缺血性脑中的细胞死亡。 然而，解决新生小鼠或大鼠HI脑损伤模型中mPTP的策略是 不成功因此，相同的生物物理过程，mPTP的激活，由类似的HI应激触发， 导致成熟动物的脑损伤，在未成熟动物中可能不具有机械显著性。 个脑袋我们已经推理并发现mPTP的生物物理和药理学特性被激活， 新生动物HI期间的变化与成年动物不同。在新生儿中，这些mPTP不是亲环素D（CypD） 依赖。这a）定义了在成人中具有神经保护作用的策略的新生儿失败，和B）需要 不同的治疗方法目标1.为了确定CypD非依赖性mML是否有助于SEF和细胞凋亡， 再灌注损伤。目标2.为了确定CypD的药理学调节和结构， 独立的线粒体膜泄漏。目标3.确定CypD依赖性mPT在新生儿中的作用 HI脑损伤。 我们的工作将为线粒体透化的致病作用提供第一个直接证据 在新生儿HI脑损伤模型中。这将使我们更好地了解其调节和结构功能 关系，并帮助开发针对缺氧缺血应激的脑保护的高效策略 通过直接瞄准mPTP的离子传导部分。

SUMMARY Neonatal brain injuries, hypoxia-ischemia (HI) brain injury is one of the leading causes of disability in children. Mitochondrial dysfunction due to activation of permeability transition pore (mPTP) has been implicated in cell death after HI insult but only in the mature brain. It has been proposed that mPTP is non-specific protons/ions leak across the inner mitochondrial membrane which dissipates proton motive force and renders mitochondria deficient or incapable of ATP production, often driving cellular death in the ischemic brain. However, the strategies to address mPTP in the model of HI brain injury in neonatal mice or rats were unsuccesful. Thus, an identical biophysical process, an activation of mPTP, triggered by similar HI stress contributes to the brain injury in the mature animals and may not be mechanistically significant in the immature brain. We have reasoned and found that biophysical and pharmacological properties of the mPTP activated during HI in neonates differ from that in adult animals. In neonates these mPTP are not cyclophilin D (CypD) dependent. This a) defines neonatal failure of the strategies which are neuroprotective in adults and b) require a different therapeutic approach. Aim 1. To determine if CypD-independent mML contributes to SEF and cellular injury during reperfusion. Aim 2. To determine the pharmacological regulation and structure of CypD- independent mitochondrial membrane leaks. Aim 3. To determine the role of CypD-dependent mPT in neonatal HI brain injury. Our work will provide the very first direct evidence for pathogenic role of mitochondrial permeabilization in neonatal HI brain injury models. This will allow us to better understand its regulation and structure function relationship and help to develop highly efficient strategies of brain protection against hypoxic ischemic stress by direct targeting of the ion-conducting parts of the mPTP.